Yeast study suggests faulty proofreading is not to blame for link between cancer and DNA polymerase ε variants.

Accurate DNA replication is a matter of life and death. The polymerases responsible for replicating DNA have built-in safeguards to defend genome integrity, including proofreading activities to correct their own errors. Abnormally error-prone variants of DNA polymerase ε are linked to several types of cancer, and a popular hypothesis is that this is due to diminished proofreading ability. But new evidence published in G3 suggests otherwise.

In a yeast study of several mutant forms of DNA polymerase ε (Polε) associated with cancers, Barbari et al. show that the increased mutation rates of these wayward polymerases may not result from weakened proofreading alone. In fact, the vast majority of Polε exonuclease domain variants the group studied increased the yeast’s mutation rate more than a Polε variant that completely lacked proofreading ability did. Previous in vitro studies also showed that although the exonuclease activity Polε uses to excise mistakes is reduced in most of these variants, it is not eliminated. This means there must be other problems with these cancer-linked variants, the nature of which remain a mystery for now—though one clue is that they have amino acid substitutions in the DNA-binding cleft of Polε’s exonuclease domain.

The researchers also observed a correlation between the amount a Polε variant increased the yeast mutation rate and how common the variant was in tumors from a set of studies involving over 13,000 cases. In contrast, previous research found vastly different incidences in tumors among variants with similar impacts on exonuclease activity, providing further evidence that proofreading defects aren’t behind all cancers linked to faulty Polε. Barbari et al. don’t make any bold claims about what does cause these cancers, but given that 6% of colorectal tumors and 7% of endometrial tumors have Polε mutations, it’s clear further efforts must be dedicated to finding out.